Antiviral medications Lecture 9 Flashcards
General concepts and 5 major categories antiviral medications are used for clinical treatment
viruses are obligate intracellular parasites composed of either DNA or RNA wrapped in a protein nucleocapsid
herpes family viruses: varicella (chicken pox), Zoster (shingles), encephalitis, oral and genital
cytomegalovirus: transplant patients, AIDS/ immunosuppressed patients
Influenza: Types A and B (majority A)
Respiratory syncytial virus: RSV bronchiolitis in children
HIV: systemic destruction of helper t cells
Goal of antiviral therapy
to inhibit or eliminate teh activity of a virus with minimal effect on host function
Target therapy include: interference of attachment to the host cell membrane and entry into the host cell. Inhibiting the process of transcription or translation. Interference of viral assembly.
Acyclovir MoA
after uptake by an infected cell, acyclovir is phosphorylated to the inactive monophosphate form by a virus specific thymidine kinase and the to the activated triphosphate form my cellular enzymes. The triphosphate form then inhibits viral DNA polymerases and competes with deoxyguanosine triphosphate. This triphosphate lacks the 3 hydroxyl group necessary for insertion of the next nucleotide int he growing DNA chain thus acts as a chain terminator.
Acyclovir Pharmacokinetics
Renal elimination (60-90%)= adjustment required
bioavailability= 10-30%
Half life = 2-20 hours (renal function dependent)
Good CSF penetration
Excellent placenta and umbilical cord penetration
Acyclovir AE
Well tolerated by most patients
the intravenous formulation can result in phlebitis or in inflammation at the site of infusion
reversible renal toxicity due to crystalline nephropathy occurs in 5-10% of patient receiving the IV formulation (more common with high douse bolus infusions).
GI (N,V,D- likely dose of age dependent)
CNS (HA, Lethargy, tremors, hallucinations, and seizures)
hepatic (hyperbilirubinemia, jaundice, and hepatitis have been reported)
Acyclovir Clinical use
best result if herapy is started within 72 hours of first lesion/rash for herpes
primary 10 days of tx episodes of genital herpes simplex
recurrent 5 days of tx episodes of genital herpes simplex
suppression of frequent recurrences (>6 times per year)
IV formulation for encephalitis (10mg/kg q8Hrs)
herpes zoster (toxicity resistance, and cost vs postherpetic neuralgia). Best results if used early in rash presentation
not effective for cytomegalovirus infections
Valcylovir general and pharmacokinetics
prodrug of acyclovir- L valyl ester of acyclovir
Pharm: after absorption, valacyclovir is rapidly and virtually completely converted to acyclovir via first pass intestinal/epatic metabolism and hydrolysis
excellent bioavailabiltiy (~70%) produces similar levels to IV acyclovir.
Valcyclovir AE and clinical use
high dose have been associated with confusion, hallucinations, nephrotoxicity, and uncommon but severe thrombocytopenia syndromes.
Clinical use: herpes zoster tx, HSV tx and suppression in immunocompetent patients, recurrent herpes simplex suppression in HIV infected patients. Advantages over acyclovir: less frequent dosing (BID vs TID 5x a day)
Ganiciclovir Description and MoA
acyclic nucleoside analogues of guanine similar to acyclovir
MoA: Metabolized by thymidine kinase and other enzymes to triphosphate analog which inhibits DNA polymerase and incorporates into viral DNA. Preferntially phosphorylated to active drug in CMV infected mammalian cells.
Ganicyclovir Pharmocokinetics
In virtor, ganiciclovir is at least 10 times more potent than acyclovir in the inhibiton of CMV and epstein barr and equal to acyclovir for herpes simplex and varicella zoster.
oral bioavalability= 6-9%
Ganciclovir AE and clinical use
Bone marrow suppression- mainly neutropenia and to a lesser degree thrombocytopenia and anemia. Bone marrow suppression in usually reversible with dosage reduction/therapy discontinuation and seems to be more common in patients with AIDS over solid organ transplant patients
CNS (HA, behavioral change)
GI (nausea and vomiting)
Clinical uses: CMV retitinits TX. COMV prophylaxis in transplant patient and advanced HIV infections. PO formulation approved for prophylaxes therapy and after appropriate induction therapy with IV formulation. Other IV FDA indications inclue esophagitis, gastritis, and colitis. Intravitreal ganciclovir is a surgically implated devices exclusively for CMV retinits in atients with AIDS.
Valganciclovir
Prodrug of ganiclovir
Bioavailibilty=60%. Increased with high fat meals. renally excreted requiring renal adjustment.
Valganciclovir AE and clinical uses
Bone marrow suppression- mainly neutropenia and to a lesser degree thrombocytopenia and anemia. Bone marrow suppression in usually reversible with dosage reduction/therapy discontinuation and seems to be more common in patients with AIDS over solid organ transplant patients
CNS (HA, behavioral change)
GI (nausea and vomiting)
Clinical use: CMV retinitis, CMV prophylaxis
Peniclovir: Pharmacokinetics and MoA
Acyclic guanine nucleoside analog
Pharmacokinetics: only available in the US as a 1% topical cream.
MoA: Similar to acyclovir. Viral thymidine kinase phosphyrlates penciclovir to monophosphate form which, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and there fore replication are selectively inhibited.
Peniciclovir: AE and clinical uses
AE: application site irritation. HA?
Clinical use: HSV (cold sores) apply every 2 hours while awake for 4 days to potentially reduce healing time, viral shedding and pain.
Famciclovir
Descrption Prodrug of penciclovir.
MoA: similar to acyclovir
Pharmacokinetics: Bioavailability= 65-77%. Renally excreted requiring dose reductions.
AE: CNS (HA), GI (N,V,D)
Clinical use: Herpes zoster (shingles) tx. Best results start with 72 hours of rash onset. HSV tx or suppression of immunocompotent patient. Recurrent mucocutaneous HSVS tx in HIV patients.
Cidofovir MoA
speculated that cidofovir diphsosphate interacts with DNA polyemerase either as an alterantive substrate (incorporation at the 3’ end or within interior of DNA chain) or as a competitive inhibitor (with respect to the normal substrate dCTP)
it is unlike acyclovir or ganciclovir, phosphorylation of cidofovir to its active metabolite does not depend on virus specific thymidine kinase
Cidofovir AE and CLinical use
AE: Highly nephrotoxic (avoid use in patients with SCr > 1.5 mg/dl or higher). Misc: neutropenia, ocular hypotony, and metabolic acidosis
Clinical uses: must be administred with probenecid and normal saline to decrease chances of nephrotoxicity. Dose 5 mg/kg once weekly for two weeks then every other week until progression of retinits or adverse affects. Reversed for CMV retiniits in AIDS patients who have failed or are intolerant to ganciclovir and foscarnet.
Foscarnet MoA
MoA: competes for pyrophosate site in viral but not human DNA polyerase and revese transcrptase.
Foscarnet is an orgnic phosphate that does not require phosphorylation by thymidine kinase, thus remains effective against many strains
Foscarnet AE:
Nephortoxic, electrolytes (severe electrolyte distrbances), CNS (seizures, fever), hematologic (anemia, neutropenia), GI (N/V/D), Cardiology (EKG changes, 1st degree AV block, hyper and hypotension.)
Foscarnet clinical uses
second line agent due to high incidences of AE
CMV retinits in patients with AIDS (combo with ganciclovir in recurrence in superior)
acyclovir resistant mucocutaneous herpes simplex in immunosuppressed.
Lamivudine description and MoA
Originally studied and marketed as an antiretroviral agent (HIV)
MoA: Metabolized intracellular to dideoxynucleotide triphosphate (DDATP) which inhibits reverse transcrptase and incorporates into viral DNA. Subsequent nucleotides fail to bind to ddATP becaues it lacs the necssary free 3 hydroxyl group, thus DNA chain termination.
Lamivudine: AE and clinical use
AE: black box warning: lactic acidosis and severe heptaomegaly (fatty liver statosis). GI (diarrhea), CNS (HA, fatiuge insomnia, peripheral neurpathy), musculoskeletal arthralgias, dermatolgoic rash
Clinical use: Hep B virus. Make sure to rule out HIV infection first. HIV (more treatments options later).
Ribavarin MoA and Pharmacokinetics
MoA: Unknown
Pharmacokinetics: bioavailibilty 50%. Food increases absorption substantially. Half life 200-300 hours at statdy state. Reneally eliminated use with caution to Cr Cl < 50 ml/min
Ribavarin AE and clinical use
AE: anemia (dose related). Combination with interferon increases the risk of fatigue, rash, pruritius, depression, esp anemia which leads to a high precentage of discontinuation of treatment early.
CLinical uses: respiratory syncytial virus bronchiolitis and pneumonia in hospitalizzed children. Hep C (standard treatment in combination with intereron alpha 2a or 2b). Genotype 1 requires 48 weeks; genotype 2 and 3 rquires 24 weeks of therapy.
Imiquimod
topical treatment of condylomata acuminate (genital warts)
induces local interferon alpha, beta, gamma, and TNF alpha > reduced viral load/wart size.
Apply 3 times a week for up to 16 weeks > complete clearance in 50% of patients
relapses are not uncommon after tx.
Amantadine and rimantidine
MoA: prevents virus from entering susceptible cells
CNS AE are worse with amantadine compared to rimantidin (anxiety, nervousness, confusion, and insomnia.)
amantadine rrequires renal adjustment for renal dysfunction whereas rimatadine does not
both are used for prophylaxis adn treatment of influeza A
for treatment of influenza A, it is important to start therapy within the first 48 hours of symptoms.
amantadines’ ability to treat parkinsonism was discovered serendipitously
Neuroamidase inhibitors Osteltamivir, Zanamivir
MoA: speicfic inhibitor of influenza virus neroaminidase which is required for release of the virus from infected cells leading to a reduction in spread of the virus
OSteltamivir AE: nausea, emesis, and abdominal discomfort most likely due to local irritation. These side effects typically resolve within 1-2 days are mild to moderate in nature and can be minimized by taking ostetamivir with food.
Zanamivir is an oral inhalation of dry powder typically well tolerated: however, reports of wheezing and bronchospasm in patinets without known airway disease have occurred. Use of zanamivir is discouraged in COPD and asthma patient due to the risk of seriious adverse events.
Both are effective for the prevention and treatment of both influenza A and B.
